A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3′termini of the linear proviral DNA; covalent joining of the recessed 3′OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner et al., Nature 1985, 313: 277]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh et al., EMBO J. 1985, 4: 1267; Power et al., Science 1986, 231: 1567; Pearl et al., Nature 1987, 329: 351]. All three enzymes have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhbitors such as indinavir and nelfinavir. The compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication. The inhibition of integrase in vitro and of HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells. The particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication.
The following references are of interest as background:
Hart, J. Chem. Soc. 1954, 1879-1882 describes the amination, hydroxylation, oxidation and chlorination of 1,5-naphthyridine.
Oakes et al., J. Chem. Soc. 1958, 204-208 discloses the preparation of certain 2,4-disubstituted 1,5-naphthyridines including 2,4-dihydroxy-1,5-naphthyridine.
McCaustland et al., J. Heterocyclic Chem. 1970, 7: 467-473 discloses the preparation of 7-chloro-2,4-dihydroxy-1,5-naphthyridine.
Buckle et al., J. Med. Chem. 1975, 18: 726-732 discloses the preparation of 4-hydroxy-3-nitro-1,5-naphthyridin-2(1H)-one by direct nitration of the corresponding ketoamide.
Dunn, Z. Chem. 1990, 30: 20-21 discloses the preparation of 4-amino-3-ethoxycarbonyl-1,5-naphthyridin-2(1H)-one by heating diethyl malonate, sodium ethoxide, and 3-amino-2-cyanopyridine under reflux.
Chen et al., J. Heterocyclic Chem. 1993, 30: 909-912 discloses the preparation of 4-hydroxy-3-(o-methoxyphenyl)-1,5-naphthyridin-2(1H)-one by refluxing the ethyl ester of 3-(o-methoxybenzylcarbonylamino)pyridine-2-carboxylic acid with sodium ethoxide in benzene.
Zografos et al., J. Org. Chem. 2001, 66: 4413-4415 discloses the preparation of certain 4-hydroxy-1,8-naphthyridin-2-ones by reacting a pyrido[2,3-d][3,1]oxazin-4-one with the anion of a beta-ketoester formed by treatment with t-BuOK.
U.S. Pat. No. 4,996,213 discloses certain 4-amino-3-carboxy-1,5-naphthyridine derivatives. The derivatives are disclosed to have nervous system affecting properties.
U.S. Pat. No. 5,294,620 discloses certain 1,6-naphthyridin-2-one derivatives having angiotensin D antagonist activity.
WO 96/11198 and WO 96/11199 disclose certain 4-hydroxy-1,8-naphthyridin-2-one derivatives
WO 95/00511 discloses certain 4-(phenyl- or pyridyl- or pyriridinyl-amino)-1,5-naphthyridine derivatives. The derivatives are disclosed to be anti-rheumatic agents.
WO 02/30930 (Publication of International Application No. PCT/US 01/31456, filed Oct. 9, 2001) discloses certain 8-hydroxy-1,6-naphthyridine-7-carboxamides which are HIV integrase inhibitors useful, inter alia, for treating HIV infection and AIDS.